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1.
Drug Deliv Transl Res ; 12(1): 294-305, 2022 01.
Artigo em Inglês | MEDLINE | ID: mdl-33604838

RESUMO

Biotherapeutics are highly efficacious, but the pain and inconvenience of chronic injections lead to poor patient compliance and compromise effective disease management. Despite innumerable attempts, oral delivery of biotherapeutics remains unsuccessful due to their degradation in the gastrointestinal (GI) environment and poor intestinal absorption. We have developed an orally ingestible robotic pill (RP) for drug delivery, which protects the biotherapeutic drug payload from digestion in the GI tract and auto-injects it into the wall of the small intestine as a safe, pain-free injection since the intestines are insensate to sharp stimuli. The payload is delivered upon inflation of a balloon folded within the RP, which deflates immediately after drug delivery. Here we present results from two clinical studies demonstrating the safety, tolerability and performance of the RP in healthy humans. In the first study, three versions of the RP (A, B and C) were evaluated, which were identical in all respects except for the diameter of the balloon. The RP successfully delivered a biotherapeutic (octreotide) in 3 out of 12 subjects in group A, 10 out of 20 subjects in group B and 16 out of 20 subjects in group C, with a mean bioavailability of 65 ± 9% (based on successful drug deliveries in groups A and B). Thus,  reliability of drug delivery with the RP ranged from 25 to 80%, with success rate directly related to balloon size. In a separate study, the deployment of the RP was unaffected by fed or fasting conditions suggesting that the RP may be taken with or without food. These promising clinical data suggest that biotherapeutics currently administered parenterally may be safely and reliably delivered via this versatile, orally ingestible drug delivery platform.


Assuntos
Procedimentos Cirúrgicos Robóticos , Administração Oral , Disponibilidade Biológica , Sistemas de Liberação de Medicamentos , Voluntários Saudáveis , Humanos , Reprodutibilidade dos Testes
2.
Pharmacol Res Perspect ; 7(5): e00522, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31584244

RESUMO

Biotherapeutic agents must be administered parenterally to obtain therapeutic blood concentrations, lowering patient compliance and complicating care. An oral delivery platform (ODP) was developed to deliver drugs into the small intestinal wall. This proof-of-concept study was performed in 17 anesthetized, laparotomized swine. In 8 swine weighing 17.4 ± 1.2 kg (mean ± SEM), 20 IU of recombinant human insulin (RHI) were auto-injected into the jejunal wall by placing the ODP inside the jejunum via an enterotomy. In 9 control swine weighing 17.0 ± 0.4 kg, 20 IU of RHI were injected subcutaneously. In both groups, under a 60-80 mg/dL euglycemic glucose clamp, blood glucose was measured with a handheld glucometer and serum insulin was measured using ELISA, at 10-minute intervals between -20 and +420 minutes after RHI delivery. The peak serum concentration of RHI was 517 ± 109 pmol/L in the ODP and 342 ± 50 pmol/L in the subcutaneous group (ns). The areas under the insulin concentration curves (83 ± 18 and 81 ± 10 nmol/L·min) were also similar in both groups. The mean time to peak serum concentration of insulin was 139 ± 42 minutes in the ODP and 227 ± 24 minutes in the subcutaneous group (ns). In conclusion, (a) The bioactivity of RHI was preserved after its delivery into the jejunal wall, (b) the intrajejunal route delivered insulin as rapidly and physiologically as the subcutaneous route, and (c) these pharmacokinetic and pharmacodynamic characteristics of RHI after intrajejunal delivery suggest that drugs currently administered parenterally, such as basal insulin, could be successfully delivered into the proximal intestinal wall via the ingestible capsule.


Assuntos
Insulina/administração & dosagem , Insulina/farmacocinética , Jejuno/química , Administração Oral , Animais , Glicemia/análise , Cápsulas , Feminino , Injeções Subcutâneas , Estudo de Prova de Conceito , Suínos
3.
Neurourol Urodyn ; 38(5): 1241-1249, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-30947360

RESUMO

AIM: To validate the functionality of an implantable pudendal nerve stimulator under development for Food and Drug Administration approval to restore bladder function after spinal cord injury. METHODS: In nine cats under anesthesia, two tripolar cuff electrodes were implanted bilaterally on the pudendal nerves and one bipolar cuff electrode was implanted on the right pudendal nerve central to the tripolar cuff electrode. The pudendal nerve stimulator was implanted subcutaneously on the left lower back along the lumbosacral spine and connected to the cuff electrodes. In five cats, a double lumen catheter was inserted into the bladder through the urethra to infuse saline and measure bladder pressure and another catheter was inserted into the distal urethra to perfuse and measure the back pressure caused by urethral contraction. In four cats, a bladder catheter was inserted into the bladder dome and the urethra was left open so that voiding could occur without urethral outlet obstruction. RESULTS: The implantable pudendal nerve stimulator was controlled wirelessly and successfully provided the required stimulation waveforms to different cuff electrodes. Pudendal nerve stimulation (PNS) at 5 Hz increased bladder capacity to about 200% of control capacity. PNS at 20 to 30 Hz induced large (80-100 cmH2 O) bladder contractions under isovolumetric conditions. When combined with ipsilateral or bilateral pudendal nerve block induced by 6 to 10 kHz stimulation, PNS at 20 to 30 Hz elicited low pressure (<40 cmH 2 O) efficient (70%) voiding. CONCLUSIONS: The implantable stimulator generated the required stimulation waveforms and successfully induced low pressure efficient voiding in anesthetized cats.


Assuntos
Neuroestimuladores Implantáveis , Nervo Pudendo , Micção , Animais , Gatos , Estimulação Elétrica , Eletrodos Implantados , Contração Muscular , Uretra/fisiologia , Bexiga Urinária/fisiologia
4.
Virus Genes ; 38(1): 118-28, 2009 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-19048364

RESUMO

Developing a vaccine that can differentiate infected and vaccinated animals (DIVA) is a new challenge in the design of a vaccine for porcine reproductive and respiratory syndrome virus (PRRSV). Nonstructural protein 2 (nsp2) is the single largest viral product, and it has multiple roles in polypeptide processing and replication complex formation. Using reverse genetics and an infectious PRRSV cDNA clone, we constructed several deletion mutants in the non-essential region of nsp2. One mutant, which has a 131 amino acid deletion within a relatively conserved region of nsp2, was recovered and found to produce a viable virus. The deleted region was replaced with a peptide tag encoding eight amino acids. A recombinant virus containing the 131 amino acid deletion was found to produce normal virus yields in MARC-145 cells and porcine alveolar macrophages (PAM); however, gross and micro-histopathology showed that the virus was less virulent in pigs. The 131 amino acid peptide was expressed as a recombinant protein and used to coat enzyme-linked immunosorbent assay (ELISA) plates. This peptide was recognized by sera from pigs infected with wild-type virus, but not by sera from pigs infected with the deletion mutant. The results from this study show that nsp2 is an important target for the development of marker vaccines and for virus attenuation.


Assuntos
Mutagênese Insercional , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/patogenicidade , Deleção de Sequência , Proteínas não Estruturais Virais/imunologia , Fatores de Virulência/fisiologia , Sequência de Aminoácidos , Animais , Anticorpos Antivirais/sangue , Linhagem Celular , Células Cultivadas , Ensaio de Imunoadsorção Enzimática/métodos , Pulmão/patologia , Macrófagos Alveolares/virologia , Dados de Sequência Molecular , Síndrome Respiratória e Reprodutiva Suína/patologia , Síndrome Respiratória e Reprodutiva Suína/virologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Suínos , Vacinas Marcadoras/imunologia , Proteínas não Estruturais Virais/genética , Virulência , Fatores de Virulência/genética
5.
J Am Vet Med Assoc ; 232(6): 906-12, 2008 Mar 15.
Artigo em Inglês | MEDLINE | ID: mdl-18341450

RESUMO

OBJECTIVE: To evaluate, under field conditions, the effects of a commercial porcine circovirus type 2 (PCV2) vaccine on mortality rate and growth performance in a herd infected with PCV2 that had a history of porcine circovirus disease. DESIGN: Randomized controlled clinical trial. ANIMALS: 485 commercial, cross-bred, growing pigs. PROCEDURES: Prior to weaning, pigs were randomly assigned within litter to a vaccination or unvaccinated control group. Pigs in the vaccination group were given a commercial PCV2 vaccine at weaning and 3 weeks later. Mortality rate was recorded, and pigs were weighed prior to vaccination, when moved from the nursery, and prior to marketing. Infection status was assessed by serologic testing and detection of viral DNA in serum. RESULTS: Compared with control pigs, pigs vaccinated against PCV2 had a significantly lower mortality rate during the finishing phase, significantly higher average daily gain during the finishing phase, and significantly lower likelihood of being lightweight at the time of marketing. For vaccinated pigs, overall mortality rate was reduced by 50% and average daily gain during the finishing period was increased by 9.3%. At the time of marketing, vaccinated pigs weighed an average of 8.8 kg (19.4 lb) more than control pigs, without any difference in days to marketing. Serum PCV2 antibody titers increased in control pigs, and PCV2 DNA was detected, indicating active PCV2 infection. CONCLUSIONS AND CLINICAL RELEVANCE: Results suggested that vaccination against PCV2 was effective at reducing mortality rate and improving growth performance among pigs in a herd infected with PCV2.


Assuntos
Infecções por Circoviridae/veterinária , Circovirus/imunologia , Doenças dos Suínos/mortalidade , Doenças dos Suínos/prevenção & controle , Suínos/crescimento & desenvolvimento , Vacinas Virais/imunologia , Animais , Anticorpos Antivirais/sangue , Infecções por Circoviridae/mortalidade , Infecções por Circoviridae/prevenção & controle , Feminino , Masculino , Vacinação/veterinária , Desmame , Aumento de Peso
6.
Virus Res ; 128(1-2): 106-14, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17553585

RESUMO

The nonstructural protein 2 (nsp2) of porcine reproductive and respiratory syndrome virus (PRRSV) is the single largest protein produced during infection. The cDNA of the pCMV-129 infectious PRRSV clone was modified for accepting foreign tags by first creating unique Mlu I and SgrA I restrictions sites at nucleotide (nt) positions 3219 and 3614, respectively, within the C-terminal region of nsp2. cDNAs encoding oligo- and polypeptide tags, including FLAG, enhanced green fluorescent protein (EGFP) and luciferase were inserted into the newly created restriction sites. The results showed that only the EGFP-containing genomes were properly expressed and produced virus. EGFP fluorescence, but not EGFP immunoreactivity, was lost during passage of recombinant EGFP viruses in culture. Sequencing of a fluorescent-negative EGFP virus showed that the EGFP remained intact, except for the appearance of arginine to cysteine mutation at position 96, which may interfere with chromophore formation or function.


Assuntos
Cisteína Endopeptidases/metabolismo , Proteínas de Fluorescência Verde/metabolismo , Luciferases/metabolismo , Peptídeos/metabolismo , Vírus da Síndrome Respiratória e Reprodutiva Suína/fisiologia , Animais , Proteínas de Bactérias/metabolismo , Linhagem Celular , Cisteína Endopeptidases/genética , Desoxirribonucleases de Sítio Específico do Tipo II/metabolismo , Regulação Viral da Expressão Gênica , Proteínas de Fluorescência Verde/genética , Luciferases/genética , Microscopia Confocal , Mutagênese Sítio-Dirigida , Oligopeptídeos , Peptídeos/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/genética , Vírus da Síndrome Respiratória e Reprodutiva Suína/metabolismo , Recombinação Genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Suínos/virologia , Replicação Viral
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